57 research outputs found
Astroglial-targeted expression of the fragile X CGG repeat premutation in mice yields RAN translation, motor deficits and possible evidence for cell-to-cell propagation of FXTAS pathology
The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5′-
untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the premutation
allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia
syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in
neurons and astroglia. Previous studies recapitulated these histopathological features in neurons in a knock-in
mouse model, but without significant astroglial pathology. To determine the role of astroglia in FXTAS, we
generated a transgenic mouse line (Gfa2-CGG99-eGFP) that selectively expresses a 99-CGG repeat expansion
linked to an enhanced green fluorescent protein (eGFP) reporter in astroglia throughout the brain, including
cerebellar Bergmann glia. Behaviorally these mice displayed impaired motor performance on the ladder-rung
test, but paradoxically better performance on the rotarod. Immunocytochemical analysis revealed that CGG99-
eGFP co-localized with GFAP and S-100ß, but not with NeuN, Iba1, or MBP, indicating that CGG99-eGFP
expression is specific to astroglia. Ubiquitin-positive intranuclear inclusions were found in eGFP-expressing glia
throughout the brain. In addition, intracytoplasmic ubiquitin-positive inclusions were found outside the nucleus in
distal astrocyte processes. Intriguingly, intranuclear inclusions, in the absence of eGFP mRNA and eGFP fluorescence,
were present in neurons of the hypothalamus and neocortex. Furthermore, intranuclear inclusions in both neurons and
astrocytes displayed immunofluorescent labeling for the polyglycine peptide FMRpolyG, implicating FMRpolyG in the
pathology found in Gfa2-CGG99 mice. Considered together, these results show that Gfa2-CGG99 expression in mice is
sufficient to induce key features of FXTAS pathology, including formation of intranuclear inclusions, translation of
FMRpolyG, and deficits in motor function
A neuroligin-3 mutation implicated in autism causes abnormal aggression and increases repetitive behavior in mice
The Role of Anabolic Androgenic Steroids in Disruption of the Physiological Function in Discrete Areas of the Central Nervous System
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